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2.
BMC Infect Dis ; 24(1): 873, 2024 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-39198721

RESUMEN

Substantial advances have been made in the development of promising HIV vaccines to eliminate HIV-1 infection. For the first time, one hundred of the most submitted HIV subtypes and CRFs were retrieved from the LANL database, and the consensus sequences of the eleven HIV proteins were obtained to design vaccines for human and mouse hosts. By using various servers and filters, highly qualified B-cell epitopes, as well as HTL and CD8 + epitopes that were common between mouse and human alleles and were also located in the conserved domains of HIV proteins, were considered in the vaccine constructs. With 90% coverage worldwide, the human vaccine model covers a diverse allelic population, making it widely available. Codon optimization and in silico cloning in prokaryotic and eukaryotic vectors guarantee high expression of the vaccine models in human and E. coli hosts. Molecular dynamics confirmed the stable interaction of the vaccine constructs with TLR3, TLR4, and TLR9, leading to a substantial immunogenic response to the designed vaccine. Vaccine models effectively target the humoral and cellular immune systems in humans and mice; however, experimental validation is needed to confirm these findings in silico.


Asunto(s)
Vacunas contra el SIDA , Biología Computacional , Infecciones por VIH , VIH-1 , Vacunología , Humanos , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/genética , Animales , Biología Computacional/métodos , Vacunología/métodos , VIH-1/inmunología , VIH-1/genética , Ratones , Infecciones por VIH/prevención & control , Infecciones por VIH/inmunología , Simulación de Dinámica Molecular , Epítopos de Linfocito T/inmunología , Epítopos de Linfocito T/genética , Genoma Viral , Epítopos de Linfocito B/inmunología , Epítopos de Linfocito B/genética , Desarrollo de Vacunas
3.
Artículo en Inglés | MEDLINE | ID: mdl-39110331

RESUMEN

The development of biocompatible wound dressings containing therapeutic agents to accelerate wound healing is an interesting field of study in biomedical sciences. Polyvinyl alcohol (PVA) nanofibers were loaded with zinc oxide nanoparticles (ZnO NPs) and curcumin (Cur) through electrospinning. The dressings were characterized by SEM and XRD and FTIR. The antioxidant, antibacterial, and cytotoxic activities Cur/ZnO/PVA nano dressing were evaluated using DPPH radical scavenging assay, disc diffusion method, and MTT assay, respectively. Cur/ZnO/PVA nano dressing showed sustained Cur release about 19.7% and 61.1% after 8h and 168h, respectively. Cur/ZnO NPs/PVA mixture had higher antioxidant potential than PVA, ZnO NPs, and Cur. The dressing showed a good antibacterial effect. The in vivo wound healing effect of different types of prepared dressings, including PVA, Cur/PVA, Cur/ZnO/PVA, and ZnO/ PVA nanofibers, was also investigated. PVA dressing containing Cur/ZnO NPs resulted in the highest increase of wound contraction in rats. The assembly of Cur and ZnO NPs on PVA nanofibers could propose as an effective delivery method to improve the wound healing process. The investigated wound dressing could be commercialized and used on a large scale after proper further studies, including clinical trials.

4.
Artículo en Inglés | MEDLINE | ID: mdl-38967072

RESUMEN

AIMS: Here, we will review different bacterial causes of respiratory tract infections and discuss the available diagnostic methods. Moreover, we will provide some recently published patents and newer techniques, such as respiratory panels and omics approaches, and express the challenges in this path. BACKGROUND: Respiratory tract infections (RTIs) include those infections that can lead to the involvement of different respiratory parts, including the sinuses, throat, airways, and lungs. Acute respiratory tract infection is the leading cause of death from infectious illnesses worldwide. According to the World Health Organization, 1.6 to 2.2 million deaths have occurred due to acute respiratory infections in children under five years of age. About 4 million people die annually from respiratory infections, 98% of which are caused by lower respiratory infections. RESULTS: Depending on the type of pathogen, the severity of the infection can vary from mild to severe and even cause death. The most important pathogens involved in respiratory tract infections include Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. The symptoms are often similar, but the treatment can vary greatly. Therefore, correct diagnosis is so important. There are several methods for diagnosing respiratory infections. Traditional tests include the culture of respiratory samples, considered the primary tool for diagnosing respiratory infections in laboratories, and less common standard tests include rapid and antigenic tests. It is essential to think that the culture method is reliable. In the original method of diagnosing respiratory infections, some bacteria were challenging to grow successfully, and many clinical laboratories needed to be equipped for viral cultures. Another issue is the time to get the results, which may take up to 7 days. Rapid and antigenic tests are faster but need to be more accurate. CONCLUSION: The clinical laboratories are trying to be equipped with molecular methods for detecting respiratory pathogens and identifying the genetic material of the infectious agent in these new methods as the primary method in their agenda.

5.
Bioact Mater ; 38: 540-558, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38872731

RESUMEN

Bacteria can be programmed to deliver natural materials with defined biological and mechanical properties for controlling cell growth and differentiation. Here, we present an elastic, resilient and bioactive polysaccharide derived from the extracellular matrix of Pantoea sp. BCCS 001. Specifically, it was methacrylated to generate a new photo crosslinkable hydrogel that we coined Pantoan Methacrylate or put simply PAMA. We have used it for the first time as a tissue engineering hydrogel to treat VML injuries in rats. The crosslinked PAMA hydrogel was super elastic with a recovery nearing 100 %, while mimicking the mechanical stiffness of native muscle. After inclusion of thiolated gelatin via a Michaelis reaction with acrylate groups on PAMA we could also guide muscle progenitor cells into fused and aligned tubes - something reminiscent of mature muscle cells. These results were complemented by sarcomeric alpha-actinin immunostaining studies. Importantly, the implanted hydrogels exhibited almost 2-fold more muscle formation and 50 % less fibrous tissue formation compared to untreated rat groups. In vivo inflammation and toxicity assays likewise gave rise to positive results confirming the biocompatibility of this new biomaterial system. Overall, our results demonstrate that programmable polysaccharides derived from bacteria can be used to further advance the field of tissue engineering. In greater detail, they could in the foreseeable future be used in practical therapies against VML.

6.
Heliyon ; 10(9): e29850, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38707385

RESUMEN

A series of ethyl 2-amino-7-methyl-5-oxo-4-phenyl-4,5-dihydropyrano[4,3-b]pyran-3-carboxylate derivatives (4a-j) bearing different substitutions on the C4-phenyl ring was synthesized. The anti-proliferative activity of all the synthesized compounds was assessed against two human cancer-cell lines, including SW-480 and MCF-7, by using MTT method. Derivatives 4g, 4i, and 4j, possessing 4-NO2, 4-Cl, and 3,4,5-(OCH3)3 substitutions, were found to be the most potent compounds against both cell lines. The obtained IC50 values for 4g, 4i, and 4j were 34.6, 35.9, and 38.6 µM against SW-480 cells and 42.6, 34.2, and 26.6 µM against MCF-7 cells, respectively. Evaluation of the free radical scavenging potential of the compounds against DPPH radicals showed the highest result for compound 4j with an EC50 value of 580 µM. Molecular docking studies revealed the compounds were well accommodated within the binding site of cyclin-dependent kinase-2 (CDK2) with binding energies comparable to those of DTQ (the co-crystallized inhibitor) and BMS-265246 (a well-known CDK2 inhibitor). Molecular dynamics simulation studies confirmed the interactions and stability of the 4g-CDK2 complex. All derivatives, except 4g, were predicted to comply with the drug-likeness rules. Compound 4j may be proposed as an anti-cancer lead candidate for further studies due to the promising findings from in-silico pharmacokinetic studies, such as high GI absorption, not being a P-gp substrate, and being a P-gp inhibitor. Density functional theory (DFT) analysis was performed at the B3LYP/6-311++G (d,p) level of theory to examine the reactivity or stability descriptors of 4d, 4g, 4i, and 4j derivatives. The highest value of energy gap between HOMO and LUMO and thermochemical parameters were obtained for 4i and 4j.

7.
Heliyon ; 10(7): e28167, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38560206

RESUMEN

Cancer remains a challenging disease worldwide, necessitating innovative approaches to better comprehend its underlying molecular mechanisms and devise effective therapeutic strategies. Over the past decade, microRNAs (miRNAs) have emerged as crucial players in cancer progression due to their regulatory roles in various cellular processes. Moreover, the involvement of unwanted soluble receptors has gained increasing attention because they contribute to tumorigenesis or drug resistance by disrupting normal signaling pathways and neutralizing ligands. This comprehensive review explores the intricate interplay between miRNAs and unwanted-soluble receptors in the context of cancer biology. This study provides an analysis of the regulatory interactions between miRNAs and these receptors, elucidating how miRNAs can either suppress or enhance their expression. MiRNAs can directly target receptor transcripts, thereby regulating soluble receptor levels. They also modulate the proteolytic cleavage of membrane-bound receptors into soluble forms by targeting sheddases, such as ADAMs and MMPs. Furthermore, the review delves into the therapeutic potential of manipulating miRNAs to modulate unwanted soluble receptors. Various strategies, including synthetic miRNA mimics or anti-miRNAs, hold promise for restoring or inhibiting miRNA function to counteract aberrant receptor activity. Moreover, exploring miRNA-based delivery systems may provide targeted and precise therapies that minimizing off-target effects. In conclusion, this review sheds light on the intricate regulatory networks involving miRNAs and unwanted soluble receptors in cancer biology thereby uncovering novel therapeutic targets, and paving the way for developing innovative anti-cancer therapies.

8.
Int J Biol Macromol ; 266(Pt 2): 131231, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38554918

RESUMEN

The enormous potential of multifunctional bilayer wound dressings in various medical interventions for wound healing has led to decades of exploration into this field of medicine. However, it is usually difficult to synthesize a single hydrogel with all the required capabilities simultaneously. This paper proposes a bilayer model with an outer layer intended for hydrogel wound treatment. By adding gelatin methacrylate (GelMA) and tannic acid (TA) to the hydrogel composition and using polyvinyl alcohol-carboxymethyl chitosan (PVA-CMCs) foam layer as supports, a photocrosslinkable hydrogel with an optimal formulation was created. The hydrogels were then examined using a range of analytical procedures, including mechanical testing, rheology, chemical characterization, and in vitro and in vivo tests. The resulting bilayer wound dressing has many desirable properties, namely uniform adhesion and quick crosslinking by UV light. When used against Gram-positive and Gram-negative bacterial strains, bilayer wound dressings demonstrated broad antibacterial efficacy. In bilayer wound dressings with GelMA and TA, better wound healing was observed. Those without these elements showed less effectiveness in healing wounds. Additionally, encouraging collagen production and reducing wound infection has a major therapeutic impact on wounds. The results of this study could have a significant impact on the development of better-performing wound dressings.


Asunto(s)
Vendajes , Quitosano , Gelatina , Hidrogeles , Metacrilatos , Alcohol Polivinílico , Cicatrización de Heridas , Alcohol Polivinílico/química , Gelatina/química , Gelatina/farmacología , Cicatrización de Heridas/efectos de los fármacos , Hidrogeles/química , Hidrogeles/farmacología , Animales , Quitosano/química , Quitosano/análogos & derivados , Quitosano/farmacología , Metacrilatos/química , Metacrilatos/farmacología , Piel/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Taninos/química , Taninos/farmacología , Reactivos de Enlaces Cruzados/química , Regeneración/efectos de los fármacos , Ratones , Ratas
9.
Artículo en Inglés | MEDLINE | ID: mdl-38526660

RESUMEN

Due to its spore-forming ability, Bacillus coagulans has advantages over the other non-spore-forming probiotics. Among them, survival and stability during food processing and storage, resistance to acid pH, and digestive enzymes are important. However, there are few studies on the quality and amount of sporulation in B. coagulans. This study investigated the spore densities and formation efficiency of B. coagulans. The optimal medium formulation consisted of yeast extract (1.00 g L-1), potassium acetate (20.00 g L-1), and MnSO4 (0.01 g L-1 and 0.03 g L-1). After reaching the optimal medium, a response surface regression equation was established based on the results of central composite design (CCD) experimental designs to optimize time, temperature, and pH parameters. The predicted results thus obtained were in good agreement (R2 = 95.19%) with the results obtained by performing experiments. Multiple regression analysis and analysis of variance (ANOVA) showed that pH is negative, and temperature and time dose are positive factors. The maximum spore cell densities by optimization plots have obtained 9.80 log at temperature 83.77 °C, pH 3.05, and time 111.19 h, considering that B. coagulans needs special environmental and cellular conditions to enter the sporulation stage. In this study, the composition of the culture medium and factors such as temperature, time, and pH were considered influencing factors in B. coagulans sporulation.

10.
J Cosmet Dermatol ; 23(6): 2156-2169, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38406887

RESUMEN

BACKGROUND: Acne is a common skin issue that typically occurs during adolescence. It causes long-lasting redness and swelling in the skin. An alternative approach to treating acne could involve using a cosmetic facial mask containing herbal ingredients such as Curcumin and Rosa Damascena extract for its antibacterial properties. AIMS: This study aims to create and try out a peel-off mask gel made from Curcumin and R. Damascena extract. This gel is intended to have the ability to kill bacteria such as Staphylococcus aureus, Escherichia coli, and Propionibacterium acnes and remove dead cells from the skin surface. METHODS: The peel-off mask was made using polyvinyl alcohol (PVA) in 8% and 10% as solidifier. The evaluation of peel-off masks comprises the examination of physiochemical and mechanical aspects. Furthermore, their longevity, effectiveness, and antibacterial properties are also considered. RESULTS: The white color, pleasant smell, and soft texture were the defining features of the peel-off gel mask. The changes in PVA affect the pH level, thickness, and how quickly the peel-off mask dries. The stability test found that the peel-off mask had no significant physical changes when exposed to freezing and thawing. However, there were some differences in color and separation when using the real-time method. A prepared peel-off mask containing 10% PVA and curcumin works best against P. acne. The amount of PVA in the formula affected the physical and chemical qualities, but it did not impact on the antibacterial abilities of the peel-off mask gel. The best formula that gives the best results uses 10% PVA + curcumin. CONCLUSIONS: Using the Curcumin and R. Damascena extract in the creation of the peel-off mask gel ensures its efficacy and safety for skin application.


Asunto(s)
Acné Vulgar , Antibacterianos , Antioxidantes , Curcumina , Extractos Vegetales , Rosa , Staphylococcus aureus , Curcumina/farmacología , Curcumina/administración & dosificación , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Rosa/química , Humanos , Antibacterianos/farmacología , Antibacterianos/administración & dosificación , Antioxidantes/farmacología , Antioxidantes/administración & dosificación , Acné Vulgar/tratamiento farmacológico , Acné Vulgar/microbiología , Staphylococcus aureus/efectos de los fármacos , Propionibacterium acnes/efectos de los fármacos , Alcohol Polivinílico/química , Escherichia coli/efectos de los fármacos , Crema para la Piel/administración & dosificación , Piel/efectos de los fármacos , Piel/microbiología , Pruebas de Sensibilidad Microbiana
11.
Bioorg Chem ; 145: 107207, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38402795

RESUMEN

Inhibition of α-glucosidase and α-amylase is an important target for treatment of type 2 diabetes. In this work, a novel series of pyrano[2,3-b]chromene derivatives 5a-m was designed based on potent α-glucosidase and α-amylase inhibitors and synthesized by simple chemical reactions. These compounds were evaluated against the latter enzymes. Most of the title compounds exhibited high inhibitory activity against α-glucosidase and α-amylase in comparison to standard inhibitor (acarbose). Representatively, the most potent compound, 4-methoxy derivative 5d, was 30.4 fold more potent than acarbose against α-glucosidase and 6.1 fold more potent than this drug against α-amylase. In silico molecular modeling demonstrated that compound 5d attached to the active sites of α-glucosidase and α-amylase with a favorable binding energies and established interactions with important amino acids. Dynamics of compound 5d also showed that this compound formed a stable complex with the α-glucosidase active site. In silicodrug-likeness as well as ADMET prediction of this compound was also performed and satisfactory results were obtained.


Asunto(s)
Diabetes Mellitus Tipo 2 , Inhibidores de Glicósido Hidrolasas , Humanos , Inhibidores de Glicósido Hidrolasas/química , Acarbosa , Diabetes Mellitus Tipo 2/tratamiento farmacológico , alfa-Glucosidasas/metabolismo , Simulación del Acoplamiento Molecular , Cromonas/farmacología , Cromonas/química , alfa-Amilasas , Relación Estructura-Actividad
12.
Artículo en Inglés | MEDLINE | ID: mdl-38308671

RESUMEN

With the demand for mass production of protein drugs, solubility has become a serious issue. Extrinsic and intrinsic factors both affect this property. A homotetrameric cofactor-free urate oxidase (UOX) is not sufficiently soluble. To engineer UOX for optimum solubility, it is important to identify the most effective factor that influences solubility. The most effective feature to target for protein engineering was determined by measuring various solubility-related factors of UOX. A large library of homologous sequences was obtained from the databases. The data was reduced to six enzymes from different organisms. On the basis of various sequence- and structure-derived elements, the most and the least soluble enzymes were defined. To determine the best protein engineering target for modification, features of the most and least soluble enzymes were compared. Metabacillus fastidiosus UOX was the most soluble enzyme, while Agrobacterium globiformis UOX was the least soluble. According to the comparison-constant method, positive surface patches caused by arginine residue distribution are appropriate targets for modification. Two Arg to Ala mutations were introduced to the least soluble enzyme to test this hypothesis. These mutations significantly enhanced the mutant's solubility. While different algorithms produced conflicting results, it was difficult to determine which proteins were most and least soluble. Solubility prediction requires multiple algorithms based on these controversies. Protein surfaces should be investigated regionally rather than globally, and both sequence and structural data should be considered. Several other biotechnological products could be engineered using the data reduction and comparison-constant methods used in this study.

13.
Heliyon ; 10(3): e24949, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38317872

RESUMEN

Several studies have revealed that healthcare nanomaterials are widely used in numerous areas of dentistry, including prevention, diagnosis, treatment, and repair. Nanomaterials in dental cosmetics are utilized to enhance the efficacy of toothpaste and other mouthwashes. Nanoparticles are added to toothpastes for a variety of reasons, including dental decay prevention, remineralization, hypersensitivity reduction, brightening, and antibacterial qualities. In this review, the benefits and uses of many common nanomaterials found in toothpaste are outlined. Additionally, the capacity and clinical applications of nanoparticles as anti-bacterial, whitening, hypersensitivity, and remineralizing agents in the treatment of dental problems and periodontitis are discussed.

14.
Appl Biochem Biotechnol ; 196(8): 5563-5603, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38133881

RESUMEN

Assisted reproductive technologies are key to solving the problems of aging and organ defects. Collagen is compatible with living tissues and has many different chemical properties; it has great potential for use in reproductive medicine and the engineering of reproductive tissues. It is a natural substance that has been used a lot in science and medicine. Collagen is a substance that can be obtained from many different animals. It can be made naturally or created using scientific methods. Using pure collagen has some drawbacks regarding its physical and chemical characteristics. Because of this, when collagen is processed in various ways, it can better meet the specific needs as a material for repairing tissues. In simpler terms, collagen can be used to help regenerate bones, cartilage, and skin. It can also be used in cardiovascular repair and other areas. There are different ways to process collagen, such as cross-linking it, making it more structured, adding minerals to it, or using it as a carrier for other substances. All of these methods help advance the field of tissue engineering. This review summarizes and discusses the current progress of collagen-based materials for reproductive medicine.


Asunto(s)
Colágeno , Medicina Regenerativa , Ingeniería de Tejidos , Ingeniería de Tejidos/métodos , Medicina Regenerativa/métodos , Humanos , Colágeno/química , Animales , Materiales Biocompatibles/química
15.
Biochimie ; 2023 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-37931794

RESUMEN

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that reduces postprandial glycemic excursions by enhancing insulin secretion. In this study, a new dimeric GLP-1 analogue (GLP-1cpGLP-1) was designed by inserting human insulin C-peptide (CP) in the middle of a dimer of [Gly8] GLP-1 (7-36). Then, the dimeric incretin (GLP-1cpGLP-1) was ligated to human αB-crystallin (αB-Cry) to create a hybrid protein, abbreviated as αB-GLP-1cpGLP-1. The constructed gene was well expressed in the bacterial host system. After specific chemical release from the hybrid protein, the dimeric incretin was purified by size exclusion chromatography (SEC). Finally, the RP-HPLC analysis indicated a purity of >99 % for the dimeric incretin. The secondary structure assessments by various spectroscopic methods, and in silico analysis suggested that the dimeric incretin has α-helical rich structure. The dynamic light scattering (DLS) analysis indicates that our dimeric incretin forms large oligomeric structures. This incretin analogue significantly reduced blood glucose levels in both healthy and diabetic mice while effectively triggering insulin release. The size exclusion HPLC also indicates the interaction of the new incretin analogue with human serum albumin, the main carrier protein in the bloodstream. Consistent with the results obtained from the biological activity assessments, this significant interaction indicates its potential as a viable therapeutic agent with a long-lasting effect. The results of our research represent a significant breakthrough in the successful design of an active incretin dimer capable of effectively controlling blood sugar levels and inducing insulin secretion in the realm of diabetes treatment.

16.
J Biomater Appl ; 38(5): 692-706, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37905355

RESUMEN

In the present study, the allantoin and silver nanoparticle (Ag NPs) loaded poly caprolactone/gelatin (PCL/GEL) nanofibers produced using electrospinning technique and their cyto-compatibility and wound healing activity were evaluated in vitro and in vivo. The SEM imaging revealed diameters of 278.8 ± 10 and 240.6 ± 12 nm for PCL/GEL/Ag NPs and PCL/GEL/Ag NPs/allantoin scaffolds. The Ag NPs entrapment into scaffolds was evaluated by FTIR analysis and EDX mapping. Both scaffolds containing Ag NPs and Ag NPs/allantoin exhibited valuable wound healing activity in Wistar rat animal model. The profound granulation tissue formation, high collagen deposition in coordination with low level of edema and inflammatory cells in Ag NPs/allantoin loaded scaffolds resulted in complete and mature re-epithelialization in giving the healing score (12 out of 12) equal to positive control group to the wounds treated with these scaffolds. It was concluded that the Ag NPs/allantoin loaded scaffolds regarding to their good antibacterial activity and excellent wound healing activity could be introduced as new effective wound dressing materials.


Asunto(s)
Nanopartículas del Metal , Nanofibras , Ratas , Animales , Alantoína , Ratas Wistar , Plata , Antibacterianos , Poliésteres
17.
Bioorg Chem ; 141: 106846, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37713948

RESUMEN

Herein, a novel series of 4,5-diphenyl-imidazol-α-aminophosphonate hybrids 4a-m was designed, synthesized, and evaluated as new anti-diabetic agents. These compounds were evaluated against two important target enzymes in the diabetes treatment: α-glucosidase and α-amylase. These new compounds were synthesized in three steps and characterized by different spectroscopic techniques. The in vitro evaluations demonstrated that all the synthesized compounds 4a-m were more potent that standard inhibitor acarbose against studied enzymes. Among these compound, the most potent compound against both studied enzymes was 3-bromo derivative 4l. The latter compound with IC50 = 5.96 nM was 18-times more potent than acarbose (IC50 = 106.63 nM) against α-glucosidase. Moreover, compound 4l with IC50 = 1.62 nM was 27-times more potent than acarbose (IC50 = 44.16 nM) against α-amylase. Molecular docking analysis revealed that this compound well accommodated in the binding site of α-glucosidase and α-amylase enzymes with notably more favorable binding energy as compared to acarbose.


Asunto(s)
Acarbosa , Inhibidores de Glicósido Hidrolasas , Acarbosa/farmacología , Inhibidores de Glicósido Hidrolasas/química , Simulación del Acoplamiento Molecular , alfa-Glucosidasas/metabolismo , Hipoglucemiantes/química , alfa-Amilasas/metabolismo , Relación Estructura-Actividad , Estructura Molecular
19.
BMC Microbiol ; 23(1): 257, 2023 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-37704938

RESUMEN

BACKGROUND: Enzybiotics are promising alternatives to conventional antibiotics for drug-resistant infections. Exolysins, as a class of enzybiotics, show antibacterial effects against methicillin-resistant Staphylococcus aureus (MRSA). This study evaluated a novel exolysin containing an SH3b domain for its antibacterial activity against MRSA. METHODS: This study designed a chimeric exolysin by fusing the Cell-binding domain (SH3b) from Lysostaphin with the lytic domain (LYZ2) from the gp61 enzyme. Subsequently, LYZ2-SH3b was cloned and expressed in Escherichia coli (E. coli). Finally, the antibacterial effects of LYZ2-SH3b compared with LYZ2 and vancomycin against reference and clinical isolates of MRSA were measured using the disc diffusion method, the minimal inhibitory concentration (MIC), and the minimal bactericidal concentration (MBC) assays. RESULTS: Analysis of bioinformatics showed that LYZ2-SH3b was stable, soluble, and non-allergenic. Protein purification was performed with a 0.8 mg/ml yield for LYZ2-SH3b. The plate lysis assay results indicated that, at the same concentrations, LYZ2-SH3b has a more inhibitory effect than LYZ2. The MICs of LYZ2 were 4 µg/mL (ATCC 43,300) and 8 µg/mL (clinical isolate ST239), whereas, for LYZ2-SH3b, they were 2 µg/mL (ATCC 43,300) and 4 µg/mL (clinical isolate ST239). This suggests a higher efficiency of LYZ2-SH3b compared to LYZ2. Furthermore, the MBCs of LYZ2 were 4 µg/mL (ATCC 43,300) and 8 µg/mL (clinical isolate ST239), whereas, for LYZ2-SH3b, they were 2 µg/mL (ATCC 43,300) and 4 µg/mL (clinical isolate ST239), thus confirming the superior lytic activity of LYZ2-SH3b over LYZ2. CONCLUSIONS: The study suggests that phage endolysins, such as LYZ2-SH3b, may represent a promising new approach to treating MRSA infections, particularly in cases where antibiotic resistance is a concern. But further studies are needed.


Asunto(s)
Bacteriófagos , Staphylococcus aureus Resistente a Meticilina , Staphylococcus aureus Resistente a Meticilina/genética , Escherichia coli/genética , Antibacterianos/farmacología , Vancomicina
20.
Biomed Pharmacother ; 166: 115292, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37579696

RESUMEN

Patients receiving high-dose methotrexate (HDMTX) for malignancies are exposed to diverse complications, including nephrotoxicity, hepatotoxicity, mucositis, myelotoxicity, neurological symptoms, and death. Glucarpidase is a recombinant carboxypeptidase G2 (CPG2) that converts MTX into nontoxic metabolites. In this study, the role of vector type, gene optimization, orientation, and host on the expression of CPG2 is investigated. The effectiveness of various therapeutic regimens containing glucarpidase is classified and perspectives on the dose adjustment based on precision medicine are provided. Conjugation with cell-penetrating peptides, human serum albumin, and polymers such as PEG and dextran for delivery, higher stability, and production of the biobetter variants of CPG2 is highlighted. Conjugation of CPG2 to F(ab՜)2 or scFv antibody fragments against tumor-specific antigens and the corresponding prodrugs for tumor-targeted drug delivery using the antibody-directed enzyme prodrug therapy (ADEPT) is communicated. Trials to reduce the off-target effects and the possibility of repeated ADEPT cycles by adding pro-domains sensitive to tumor-overexpressed proteases, antiCPG2 antibodies, CPG2 mutants with immune-system-unrecognizable epitopes, and protective polymers are reported. Intracellular cpg2 gene expression by gene-directed enzyme prodrug therapy (GDEPT) and the concerns regarding the safety and transfection efficacy of the GDEPT vectors are described. A novel bifunctional platform using engineered CAR-T cell micropharmacies, known as Synthetic Enzyme-Armed KillER (SEAKER) cells, expressing CPG2 to activate prodrugs at the tumor niche is introduced. Taken together, integrated data in this review and recruiting combinatorial strategies in novel drug delivery systems define the future directions of ADEPT, GDEPT, and SEAKER cell therapy and the placement of CPG2 therein.


Asunto(s)
Neoplasias , Profármacos , Humanos , Metotrexato/uso terapéutico , gamma-Glutamil Hidrolasa/genética , gamma-Glutamil Hidrolasa/uso terapéutico , Antídotos , Anticuerpos/uso terapéutico , Polímeros/uso terapéutico
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